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Background: Different approaches for treatment de-escalation are being investigated; however, the current ongoing phase III adjuvant trials with CDK4/6 inhibitors are not addressing the question if these drugs can replace multi-agent chemotherapy in high-risk early breast cancer. Here, we present the primary results of the CORALLEEN phase 2 trial, which evaluates the efficacy of ribociclib plus endocrine therapy (ET) as neoadjuvant treatment in patients with high-risk Luminal B disease. Methods: CORALLEEN is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable hormone receptor-positive (HR+)/HER2-negative breast cancer, Luminal B by Prosigna®. Other eligibility criteria include stage I-III operable breast cancer and ECOG 0-1. Patients were randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy (CT): 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel (80 mg/m2) during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens were collected for molecular characterization and evaluation of response. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. PAM50 ROR score integrates gene expression data, tumor size, and nodal status to define a low-risk group in the adjuvant setting (i.e. >90% distant relapse-free survival at 10 years). ROR-low was defined using the standard cutpoints as Citation Format: Joaquín Gavilá, Cristina Saura, Tomás Pascual, Cristina Hernando, Montserrat Muñoz, Laia Paré, Blanca González Farré, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Miriam Arumi, Neus Ferrer Tur, Alvaro Montaño, Yan Izarzugaza, Antonio Llombart Cussac, Raquel Bratos, Santiago González, Eduardo Martínez, Sergio Hoyos, Beatriz Rojas, Juan Antonio Virizuela, Vanesa Ortega, Rafael López, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Aleix Prat. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: An open-label, multicenter, two-arm, randomized study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-06.

Background: CDK4/6 inhibitors increase tumor immunogenicity in preclinical models of breast cancer and several trials combining CDK4/6 inhibitors and anti-PD1/PDL1 therapies are underway. However, immune response data in tumor samples from patients (pts) treated with CDK4/6 inhibitors are scarce. Here, we present exploratory results of the CORALLEEN trial, which evaluated the efficacy of ribociclib and endocrine therapy in patients with high-risk Luminal B disease (Gavilá et al. submitted to SABCS 2019). Methods: CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, hormone receptor positive (HR+)/HER2-negative and Luminal B by Prosigna®. Pts were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (R+L) or chemotherapy (CHT): 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. Baseline and surgical specimens were also collected for stromal tumor infiltrating lymphocyte (TIL) determination and gene expression analysis. Expression of 770 genes and 31 biological signatures were determined using the Breast360TM panel (nCounter). In order to identify genes whose expression correlated with TIL, a significance of microarrays (SAM) quantitative analysis was used with a false discovery rate (FDR) Citation Format: Nuria Chic, Blanca González Farré, Laia Paré, Tomás Pascual, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat. Immune response following neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: A correlative analysis of the SOLTI-1402 CORALLEEN phase 2 randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-01.

Summary Background In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. Methods CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I–IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0–1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov , NCT03248427 . Findings Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2–206·0). At surgery, 23 (46·9%; 95% CI 32·5–61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9–61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3–4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3–4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. Interpretation Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. Funding Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.

Biomarcadores; Cáncer de mama; Inmunoterapia Biomarcadors; Càncer de mama; Immunoteràpia Biomarkers; Breast cancer; Immunotherapy The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy. This study has received funding from Instituto de Salud Carlos III—PI19/01846 (to AP), Breast Cancer Now—2018NOVPCC1294 (to AP), Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT (to AP), Fundació La Marató TV3 201935-30 (to AP), the European Union’s Horizon 2020 research and innovation programme H2020-SC1-BHC-2018-2020 (to AP), Asociación de Cáncer de Mama Metastásico CMM_CHIARAG19_001 (to AP), Pas a Pas (to AP), Save the Mama (to AP), Fundación Científica Asociación Española Contra el Cáncer AECC_Postdoctoral17-1062 (to FB-M) and INVES19056SANS (to MiS), FERO-ghd 2020 breast cancer award (MS), and Generalitat de Catalunya Peris PhD4MD 2019 SLT008/18/00122 (to NC).

Càncer de mama; Puntuació CelTIL; Patritumab deruxtecan Cáncer de mama; Puntuación CelTIL; Patritumab deruxtecan Breast Cancer; CelTIL Score; Patritumab deruxtecan Background: Preclinical data support a key role for the human epidermal growth factor receptor 3 (HER3) pathway in hormone receptor (HR)–positive breast cancer. Recently, new HER3 directed antibody drug conjugates have shown activity in breast cancer. Given the need to better understand the molecular biology, tumor microenvironment, and mechanisms of drug resistance in breast cancer, we designed this window-of-opportunity study with the HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402). Trial Design: Based on these data, a prospective, multicenter, single-arm, window-of-opportunity study was designed to evaluate the biological effect of patritumab deruxtecan in the treatment of naïve patients with HR-positive/HER2-negative early breast cancer whose primary tumors are ≥1 cm by ultrasound evaluation. Patients will be enrolled in four cohorts according to the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. We thank Daiichi Sankyo for their provision of patritumab deruxtecan and their financial contribution to this clinical study. Pas a Pas and Save the Mama to AP. Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in Research in Reference Centers) to TP.

BACKGROUND: Metastatic breast cancer (mBC) remains an incurable disease and is the cause of nearly all deaths from breast cancer. Targeted molecular therapies and the evolving role of next-generation sequencing (NGS) technologies are increasing and may improve outcomes in breast cancer patients. However, they are not being routinely used in the clinic. One strategy to overcome the barriers of implementing NGS in the clinic is to promote the active participation of mBC patients in the management of their disease. With this in mind, we designed HOPE (SOLTI-1903), a national real-world study where patients lead their inclusion, participation and follow-up in the study through a digital tool that will guide them in every step of the journey. Our objective is empowering mBC patients and gather real-world data about the utilization of molecular information in the management of mBC. TRIAL DESIGN: Patients diagnosed with mBC who are receiving, have just received, or will receive standard treatment or treatment in a clinical trial (CT) can be included. Demographic data, disease characteristics, treatment history and quality of life data will be collected through a digital tool (DT) by the patient. Patients are encouraged to involve their physician`s in the study journey. The study is complemented by a patient empowerment program including informative workshops and precision medicine video-tutorials. A total of 600 patients will be included in Spain. Patient Journey Once patients request to participate in HOPE through the DT, a dedicated team from SOLTI will assist them in the following steps while validating that eligibility criteria are met according to data introduced by themselves. Then, patients will receive instructions via DT to go to the nearest partner local laboratory, where they will sign the study consent form. A metastatic (preferably) or primary archival tumor sample will be requested to the patient’s reference hospital and analyzed by FoundationOne®CDx. Also, a blood sample will be collected and analyzed by Guardant360. For all patients, two NGS tests will be offered (If no tissue available, only blood test will be performed). Both molecular analyses results will be reviewed during regular meetings by a Molecular Advisory Board (MAB). The MAB, based on their joint experience in clinical oncology, genomics, molecular biology, bioethics and pathology, may add some advice to these reports via DT, making comments about detected molecular alterations and adding further recommendations for specific treatment options or available CT with targeted therapies. From that moment, patients will record their disease evolution in the DT each 3 months for 2 years. The primary objective is to assess the real-world clinical practice integrating molecular profiling in the Standard of Care management of mBC patients connected through a DT. Secondary objectives include to describe genetic mutational profile of mBC, to evaluate the enrollment rate in CT of patients engaged in a patient-centered strategy for molecular tumor assessment, to asses Progression Free Survival, Overall Survival and Quality of life status among patients enrolled in CT according to the tumor’s genomic profile and those receiving standard treatment and to describe logistic feasibility of the study. This study is sponsored by SOLTI and financially supported by Novartis and two non-profit organizations: Asociación Cáncer de Mama Metastásico y Fundación Actitud frente al Cáncer. Roche and Guardant Health provide their test for all patients. Citation Format: Ana Casas, Eva Ciruelos, Mafalda Oliveira, Cristina Saura, Meritxell Bellet, Sonia Pernas, Joaquín Gavilá, Montserrat Muñoz, María Vidal, Blanca Gonzalez Farré, Juan M. Cejalvo, Rafael Lopez, Ana Vivancos, Maurizio Scaltriti, Javier S. Bofill, Isabel Blancas, Emilio Alba, Valentina Boni, Susana De la Cruz, Elena Galve, Antonia Perelló, Mireia Margelí, Jordi Canes, Pamela Céliz, Helena Masanas, Rosa Olmos, Marga Fonts, Pilar Fernandez-Pascual, Patricia Villagrasa, Aleix Prat. Solti-1903 hope: Real-world clinical practice study to assess the impact of using comprehensive genomic data on the next treatment decision making-choice in patients with locally advanced or metastatic breast cancer in Spain [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-17-01.